Adamantyl derivative as a potent inhibitor of plasmodium FK506 binding protein 35

Article abstract of DOI:10.1021/ml400306r

FKBP35, FK506 binding protein family member, in Plasmodium species displays a canonical peptidyl-prolyl isomerase (PPIase) activity and is intricately involved in the protein folding process. Inhibition of PfFKBP35 by FK506 or its analogues were shown to interfere with the in vitro growth of Plasmodium falciparum. In this study, we have synthesized adamantyl derivatives, Supradamal (SRA/4a) and its analogues SRA1/4b and SRA2/4c, which demonstrate submicromolar inhibition of Plasmodium falciparum FK506 binding domain 35 (FKBD35) PPIase activity. SRA and its analogues not only inhibit the in vitro growth of Plasmodium falciparum 3D7 strain but also show stage specific activity by inhibiting the trophozoite stage of the parasite. SRA/4a also inhibits the Plasmodium vivax FKBD35 PPIase activity and our crystal structure of PvFKBD35 in complex with the SRA provides structural insights in achieving selective inhibition against Plasmodium FKBPs.

Full text of DOI:10.1021/ml400306r

Letter
pubs.acs.org/acsmedchemlett
Adamantyl Derivative As a Potent Inhibitor of Plasmodium FK506
Binding Protein 35
Amaravadhi Harikishore,† Min Li Leow,‡ Makhtar Niang,† Sreekanth Rajan,† Kalyan Kumar Pasunooti,‡
Peter Rainer Preiser,† Xuewei Liu,‡ and Ho Sup Yoon*,†
†School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637665 Singapore
‡School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, 637731 Singapore
S
* Supporting Information
ABSTRACT: FKBP35, FK506 binding protein family member, in
Plasmodium species displays a canonical peptidyl-prolyl isomerase
(PPIase) activity and is intricately involved in the protein folding
process. Inhibition of Pf FKBP35 by FK506 or its analogues were
shown to interfere with the in vitro growth of Plasmodium
falciparum. In this study, we have synthesized adamantyl derivatives,
Supradamal (SRA/4a) and its analogues SRA1/4b and SRA2/4c,
which demonstrate submicromolar inhibition of Plasmodium
falciparum FK506 binding domain 35 (FKBD35) PPIase activity.
SRA and its analogues not only inhibit the in vitro growth of Plasmodium falciparum 3D7 strain but also show stage specific
activity by inhibiting the trophozoite stage of the parasite. SRA/4a also inhibits the Plasmodium vivax FKBD35 PPIase activity
and our crystal structure of PvFKBD35 in complex with the SRA provides structural insights in achieving selective inhibition
against Plasmodium FKBPs.
KEYWORDS: FK506 binding protein, FKBP35, peptidyl-prolyl-isomerase, immunophilin, chaperone
alaria is one of the most dreadful diseases causing an
estimated 800,000 deaths annually in the tropical and
neurotrophic activities,21 and malaria.2,22,23 These physiological
roles of FKBPs represent them as a potential target for
pharmacological intervention.
M
subtropical regions like India, Africa, Southeast Asia, and South
America.1,2 Recent incidence of parasite resistance to most
effective drug treatment regimens-artemisinin and chloroquine
pose a serious challenge for combating malaria and its clinical
treatment. FK506 or its nonimmunosuppressive derivatives
bind to Plasmodium FK506 binding protein 35 (hereafter
referred as FKBP35), inhibit its enzymatic activity, and show in
vitro growth inhibition of Plasmodium.3−5 FKBP35 is a well
characterized FKBP in Plasmodium falciparum and vivax species
possessesing an N-terminal FK506 binding domain, a tripartite
tetratricopeptide repeat (TPR) domain and a calmodulin
binding domain at its C-terminus. FKBP35 is highly
homologous to human FKBP family members like FKBP12,
FKBP51, and FKBP52 in possessing peptidyl-prolyl-isomerase
(PPIase) and chaperone activities.4,6 FKBP family members
mediate protein−protein interactions regulating various phys-
iological processes. FKBP12-FK506 binary complex interacts
with calcineurin and inhibits the dephosphorylation of
transcription factor, nuclear factor of activated T cells
(NFATc). This prevents the nuclear translocation of NFATc
and subsequent stimulation of IL-2 synthesis leading to
suppression of immune responses.7 FKBP family members
show a canonical PPIase or rotamase activity. FKBPs through
their rotamase activity play an important role in various
physiological activities like protein stability,8−10 chaperonic
activity,11,12 receptor signaling,13−15 protein trafficking,16,17
transcription,18,19 calcium homeostasis,15,20 neuroprotective,
Previous study by Braun et al., showed that a synthetic ligand
of FK506 (SLF) binds tightly to FKBP12 but lacks cellular
toxicity.5 The physiological levels of human FKBP12 levels (5
μM) are much higher in comparison to Plasmodium FKBP35
(100 nM) providing a therapeutic window to achieve selectivity
toward parasite FKBP35.5 Furthermore, lack of cellular toxicity
has further been exploited to increase the bioavailability of HIV
protease inhibitor by tethering FKBP12 ligand, SLF (Chart 1),
to amprenavir.24 Babine et al., has shown that an adamantyl-like
fragment bonded to pyridine via a sulfur atom (5, Chart 1)
binds and inhibits the enzymatic activity of FKBP12 at
micromolar range. The crystal structure of FKBP12 with this
compound revealed that the adamantyl-like fragment docks
onto the base of Trp58, whereas the distal pyridine ring
interacts with His87 residue at the β4−β5 loop.25 In this study,
we demonstrate that adamantyl derivative 4a/SRA and its
analogues bind to Plasmodium FKBD35 inhibiting its PPIase
activity as well as Plasmodium falciparum 3D7 strain growth in
vitro.
A three-step synthesis for adamantine building blocks (4a−c)
was set up starting from the corresponding acids (1a−c,
Received: August 5, 2013
Accepted: September 16, 2013
© XXXX American Chemical Society
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Chart 1. Chemical Structures of Known FKBP Ligands and
4a/Supradamal (SRA)
Table 1. Effect of Adamantyl Derivatives on Plasmodium
FKBD35 Activity
compd
R1
Pf FKBP35 IC50 (nM)
a
4a/SRA
4-pyridyl
phenyl
83 9.32 (75 6.32)
94.75 11.8
4b/SRA1
4c/SRA2
1-napthyl
49.3 6.2
a
Refers to IC50 against Plasmodium vivax FKBP35. SD (standard
deviation) represents the error from two independent experiments
performed in duplicate (n = 2).
Scheme 1). The acid was treated with thionyl chloride in the
presence of ethanol to yield its ethyl esters (2a−c). Further,
Scheme 1. Synthesis of Adamantyl Derivatives
Figure 1. Calcineurin phosphatase assay. Compound 4a (SRA)/
FK506 complexes with human FKBP had no effect on calcineurin
phosphatase activity, while FK506 complex with human FKBP12
inhibited calcineurin phosphatase activity. Calcineurin alone served as
control.
that these novel ligands do not possess the ability to inhibit
calcineurin phosphatase activity and therefore do not suppress
immune responses, unlike FK506, which inhibits the
phosphatase activity of calcineurin leading to immune
suppression.
ethyl esters (2a−c) were converted into its hydrazides (3a−c)
by using hydrazine in the presence of ethanol. Finally,
hydrazides were treated with adamantane-1-carbonyl chloride
to obtain the target molecules (4a−c). (Scheme 1).
Interaction analysis of FK506 with human and Plasmodium
FKBPs reveal a strikingly similar pattern in both the species
albeit with a few variations at the β4−β5 loop. Conserved
interaction pattern of FK506 with Plasmodium FKBP35 and
human FKBP12 further bolsters the utility of small molecule
inhibitors of FKBP12 ligands as scaffolds for achieving the
parasite FKBP35 inhibition.26−28 Our molecular modeling
studies suggested that the adamantyl derivative (Supradamal,
SRA or 4a) had a reasonably good fitness score of 52.66 when
compared to FK506 (79.77). Similar to the pipecolinyl moiety
of FK506, the adamantyl fragment is predicted to dock on to
the canonical binding site Trp78 (S1) and the linker can form
hydrogen bonding interactions with Ile75 and Tyr101 and
hydrophobic contacts with Tyr101. Thus, SRA could favor the
S2 site between α1−β5 loop and orient away from the β4−β5
loop (S3), which is involved in a number of protein−protein
interactions such as calcineurin, Inositol triphosphate IP3
receptor, and TGF-beta signaling (Supporting Information
Figure S1a). Therefore, we chose to increase the linker length
by 4-atoms in order to induce steric clashes with His87 of
human FKBP12 and to enhance the probability of binding to
Plasmodium FKBP35.
To investigate whether SRAs inhibit parasites maturation,
growth inhibition assays were carried out using 3D7 parasites.
The maturation of highly synchronized ring-infected eryth-
rocytes was monitored for an entire intraerythrocytic
developmental cycle (IDC) (48 h) in the presence of SRAs
and known P. falciparum inhibitors (chloroquine (CQ) and
artemisinin (ART)) or in absence of treatment (control).
Parasitaemia and parasite morphology were determined at 8 h
time interval. During the first 8 h (ring stage development), no
parasitaemia (Figure 2a) and morphological changes (Figure
2b) were observed between the SRA-treated, CQ-treated, and
untreated parasites, whereas a rapid decrease in parasitaemia
was observed with ART-treated parasites, in line with the
known effect of ART on ring parasites stages. Subsequently,
control parasites mature successively to trophozoite (16−24 h),
then to schizont (32−40 h) with further invasion (48 h)
(Figure 2b) leading to increased parasitaemia at 40 and 48 h
(Figure 2a). In contrast, parasitaemia of SRAs and CQ-treated
parasites decrease in a similar pattern during trophozoite
development (16−24 h) (Figure 2a) where the parasites died
and disintegrated (Figure 2b). Taken together, these results
suggest that SRA inhibitors interfere with the trophozoite stage
development.
Supradamal (SRA) and its derivatives SRA-1 and SRA-2
inhibits the Plasmodium falciparum FK506 binding domain
(FKBD35) activity significantly at nanomolar range (Table 1).
Our in vitro enzymatic assay results suggest that SRA is unlikely
to inhibit calcineurin phosphatase activity (Figure 1) signifying
To confirm the specificity of the inhibitory activity of SRAs
on trophozoite stages, we investigated the direct effect of SRAs
on highly synchronized ring, trophozoite, and schizont stage
maturation by incubating parasites with 500 nM (2× IC50,
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While this finding confirms that SRA inhibitors directly
interfere with the trophozoite development. Further studies
using chemical biology approaches with SRA may provide
further insights into the protein−protein interactions that
might be involved in its mode of action.
To understand the molecular basis of SRA interaction, we
attempted to crystallize SRA and its analogues with FKBD of
both Plasmodium falciparum and vivax FKBP35.28 Crystals with
Pf FKBD35 did not yield good quality crystals for structure
elucidation. However, the crystal screening of PvFKBD35 with
SRA gave good quality crystals. The crystallographic structure
of PvFKBD35 in complex with SRA was determined to a
resolution of 1.72 Å (atomic coordinates have been deposited
to protein data bank with PDB code 4MGV). Refined
crystallographic structure revealed a topology consisting of
seven β-stranded sheets and a short α-helix similar to the
previous FKBD35 structures.26,28,29 The electron density for
SRA (Figure 3a) was traced unequivocally in the hydrophobic
binding pocket. The hydroxyl oxygen atoms in carbonyl
hydrazide linker region of SRA make critical hydrogen bonding
contacts (Supporting Information Table S1) with the catalytic
Figure 2. Effects of SRA analogues on Plasmodium falciparum IDC.
(A) Effect of SRA on parasitemia (%) was monitored every 8 h upon
the addition of inhibitor(s) and were compared to untreated control
parasites. (B) Parasite morphology was monitored by Giemsa stain at
each time point. Illustrations of parasite morphology at 8, 16, 24, 32,
40, and 48 h after addition of inhibitor are shown. (C) Effects of SRA/
SRA1 and SRA2 on trophozoite development. Parasite morphology
was monitored by Giemsa stain at 4, 8, and 16 h after the addition of
inhibitor. During the first 4 h, no significant morphological differences
were observed between the treated and control parasites. During the
subsequent development, the control parasites progress to the next
generation (formation of mature schizont and ring), while the SRA
treated cells remain arrested at the trophozoite stage. The results show
that SRA and its derivatives mainly interfere with trophozoite stage
development.
Figure 3. Comparison of SRA-FKBD35 interactions. (A) The 2Fo-Fc
electron density map contoured at 1σ cutoff for the SRA inhibitor
(green sticks); also shown are the interacting active site residues (blue
sticks). (b) The hydrogen bonds (brown dashes) formed by SRA with
Tyr100, Ile74, and two water molecules are shown with their distances
labeled. It could be clearly seen that a network of hydrogen bonds are
made by the four atoms of SRA. The nonbonded contacts (black
dashes) are primarily made by the adamantyl ring of SRA. (c) The
electrostatic surface diagram showing the docking of SRA in the active
site pocket, with the adamantyl ring sitting deep inside the base of the
pocket with Trp77 acting like a platform. (d) Superposition of the
FK506 complex (purple) on the SRA complex, indicating three key
features (shown within circle) of SRA interactions. The adamantyl ring
overlies on the pipecolinyl ring (S1) of FK506 and the pyridine ring
on the cyclohexyl ring (S2). In addition, the allyl group (S3) of FK506
responsible for the calcineurin inhibition is seen to be completely away
from SRA. This explains the nonimmunosuppressive nature of SRA at
a molecular perspective. All the figures are in a similar orientation, with
the interacting residues labeled in panel b alone. The figure has been
generated using PyMOL.32
Supporting Information Figure 2) of each SRA analogue. No
effect was seen on ring and schizont maturation (data not
shown), while control trophozoite parasites successfully
matured to schizont stages (Figure 2c, control); the develop-
ment of SRA-treated trophozoites was impaired after 8 h of
SRA addition followed by disintegration after 16 h (Figure 2c).
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residues Tyr100 and Ile74 (Figure 3b). In addition, the two
nitrogen atoms in the linker also form hydrogen bonds with the
nearby water molecules (Figure 3b). Thus, a network of
hydrogen bonds with atoms from the trunk of the inhibitor
holds it strongly in the active site pocket. Further nonbonded
contacts (Supporting Information Table S1) predominantly by
the adamantyl ring of SRA with residues like Tyr43, Asp55,
Phe64, Val73, Trp77, Tyr100, and Phe117 lock the ligand deep
inside the pocket (Figure 3c) where Trp77 forms a platform-
like architecture (Figure 3b,c). Crystallographic complex
structure of human FKBP12-FK506-calcineurin7 reveals that
the allyl group of FK506 (the effector domain) docks into Ca2+-
calmodulin activated calcineurin and that modification of this
allyl group to either ethyl (FK520)30 or acetyl (FK1706)31
moieties had markedly hampered the inhibition of calcineurin
phosphatase activity. Superposition with the FK506 complex of
PvFKBD35 (PDB ID 3IHZ) revealed some key features of SRA
orientation and interaction. The adamantyl and pyridine rings
of SRA overlay on to the pipecolinyl and cyclohexyl rings of
FK506, respectively (Figure 3d). As SRA lacks substituent
groups onto the allyl group of FK506 (the effector domain), it
adopts an orientation that does not interfere with the
calcineurin binding region (Figure 3d). Further, the four
atom linker stabilized by a network of hydrogen bonds is
responsible for orienting the pyridine ring toward the
cyclohexyl ring of FK506. Therefore, it is evident that SRA
does not impinge the calcineurin activity, rendering it to be a
nonimmunosuppressive inhibitor (Figure 2). Additionally it
possesses stronger affinity toward the hydrophobic pocket of
FKBP due to its adamantyl group. Thus, on the basis of the
crystal structure, the molecular basis of the nonimmunosup-
pressive nature of SRA has been explained.
ACKNOWLEDGMENTS
■
The authors thank Dr. Reema Alag for helpful suggestions
during PPIase enzyme inhibition studies.
ABBREVIATIONS
■
FKBP, FK506 binding protein; FKBD, FK506 binding domain;
PPIase, peptidyl-prolyl-isomerase; CaN, calcineurin; Pf ,
Plasmodium falciparum; Pv, Plasmodium vivax; TLC, thin layer
chromatography
REFERENCES
■
(1) Gardner, M. J.; Hall, N.; Fung, E.; White, O.; Berriman, M.;
Hyman, R. W.; Carlton, J. M.; Pain, A.; Nelson, K. E.; Bowman, S.;
Paulsen, I. T.; James, K.; Eisen, J. A.; Rutherford, K.; Salzberg, S. L.;
Craig, A.; Kyes, S.; Chan, M. S.; Nene, V.; Shallom, S. J.; Suh, B.;
Peterson, J.; Angiuoli, S.; Pertea, M.; Allen, J.; Selengut, J.; Haft, D.;
Mather, M. W.; Vaidya, A. B.; Martin, D. M.; Fairlamb, A. H.;
Fraunholz, M. J.; Roos, D. S.; Ralph, S. A.; McFadden, G. I.;
Cummings, L. M.; Subramanian, G. M.; Mungall, C.; Venter, J. C.;
Carucci, D. J.; Hoffman, S. L.; Newbold, C.; Davis, R. W.; Fraser, C.
M.; Barrell, B. Genome sequence of the human malaria parasite
Plasmodium falciparum. Nature 2002, 419, 498−511.
(2) Monaghan, P.; Fardis, M.; Revill, W. P.; Bell, A. Antimalarial
effects of macrolactones related to FK520 (ascomycin) are
independent of the immunosuppressive properties of the compounds.
J. Infect. Dis. 2005, 191, 1342−1349.
(3) Bell, A.; Wernli, B.; Franklin, R. M. Roles of peptidyl-prolyl cis−
trans isomerase and calcineurin in the mechanisms of antimalarial
action of cyclosporin A, FK506, and rapamycin. Biochem. Pharmacol.
1994, 48, 495−503.
(4) Kumar, R.; Adams, B.; Musiyenko, A.; Shulyayeva, O.; Barik, S.
The FK506-binding protein of the malaria parasite, Plasmodium
falciparum, is a FK506-sensitive chaperone with FK506-independent
calcineurin-inhibitory activity. Mol. Biochem. Parasitol. 2005, 141, 163−
173.
(5) Braun, P. D.; Barglow, K. T.; Lin, Y. M.; Akompong, T.;
Briesewitz, R.; Ray, G. T.; Haldar, K.; Wandless, T. J. A bifunctional
molecule that displays context-dependent cellular activity. J. Am. Chem.
Soc. 2003, 125, 7575−7580.
(6) Galat, A. Peptidylprolyl cis/trans isomerases (immunophilins):
biological diversity−targets−functions. Curr. Top. Med. Chem. 2003, 3,
1315−1347.
In conclusion, the present study presents adamantyl
derivatives as potent inhibitors of Plasmodium FKBD35
enzymatic activity as well as trophozoite stage growth inhibition
of Plasmodium falciparum 3D7 strain. Further, our crystallo-
graphic structure complex of Plasmodium vivax with SRA
further provides insights into its mode of action and lack of
immune suppression.
ASSOCIATED CONTENT
* Supporting Information
■
(7) Griffith, J. P.; Kim, J. L.; Kim, E. E.; Sintchak, M. D.; Thomson, J.
A.; Fitzgibbon, M. J.; Fleming, M. A.; Caron, P. R.; Hsiao, K.; Navia,
M. A. X-ray structure of calcineurin inhibited by the immunophilin-
immunosuppressant FKBP12-FK506 complex. Cell 1995, 82, 507−
522.
(8) Barth, S.; Nesper, J.; Hasgall, P. A.; Wirthner, R.; Nytko, K. J.;
Edlich, F.; Katschinski, D. M.; Stiehl, D. P.; Wenger, R. H.; Camenisch,
G. The peptidyl prolyl cis/trans isomerase FKBP38 determines
hypoxia-inducible transcription factor prolyl-4-hydroxylase PHD2
protein stability. Mol. Cell. Biol. 2007, 27, 3758−3768.
S
Experimental procedures for the synthesis and characterization
of the compounds, the in vitro PPIase assay, growth inhibition
assays, crystallization, X-ray data collection, structure determi-
1
nation, refinement, and the H NMR and 13C NMR spectra of
the reported compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*(H.S.Y.) E-mail: hsyoon@ntu.edu.sg.
(9) Choi, B. H.; Feng, L.; Yoon, H. S. FKBP38 protects Bcl-2 from
caspase-dependent degradation. J. Biol. Chem. 2010, 285, 9770−9779.
(10) Jinwal, U. K.; Koren, J., III; Borysov, S. I.; Schmid, A. B.;
Abisambra, J. F.; Blair, L. J.; Johnson, A. G.; Jones, J. R.; Shults, C. L.;
O’Leary, J. C., III; Jin, Y.; Buchner, J.; Cox, M. B.; Dickey, C. A. The
Hsp90 cochaperone, FKBP51, increases Tau stability and polymerizes
microtubules. J. Neurosci. 2010, 30, 591−599.
■
Author Contributions
H.S.Y. designed the research. A.H., M.L.L., M.N., S.R., and
K.K.P. performed the research. A.H., K.K.P., M.N., S.R., P.R.P.,
X.L., and H.S.Y. analyzed the data. A.H., M.L.L., K.K.P., M.N.,
S.R., P.R.P., and H.S.Y. drafted the manuscript.
(11) Kuzuhara, T.; Horikoshi, M. A nuclear FK506-binding protein is
a histone chaperone regulating rDNA silencing. Nat. Struct. Mol. Biol.
2004, 11, 275−283.
Funding
(12) Nelson, C. J.; Santos-Rosa, H.; Kouzarides, T. Proline
isomerization of histone H3 regulates lysine methylation and gene
expression. Cell 2006, 126, 905−916.
The authors wish to thank Ministry of Health NMRC IRG
Grant (NMRC/1245/2010) for funding this work.
Notes
(13) Wang, T.; Li, B. Y.; Danielson, P. D.; Shah, P. C.; Rockwell, S.;
Lechleider, R. J.; Martin, J.; Manganaro, T.; Donahoe, P. K. The
The authors declare no competing financial interest.
D
dx.doi.org/10.1021/ml400306r | ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
immunophilin FKBP12 functions as a common inhibitor of the TGF
beta family type I receptors. Cell 1996, 86, 435−444.
(31) Price, R. D.; Yamaji, T.; Yamamoto, H.; Higashi, Y.; Hanaoka,
K.; Yamazaki, S.; Ishiye, M.; Aramori, I.; Matsuoka, N.; Mutoh, S.;
Yanagihara, T.; Gold, B. G. FK1706, a novel non-immunosuppressive
immunophilin: neurotrophic activity and mechanism of action. Eur. J.
Pharmacol. 2005, 509, 11−19.
(14) Riggs, D. L.; Roberts, P. J.; Chirillo, S. C.; Cheung-Flynn, J.;
Prapapanich, V.; Ratajczak, T.; Gaber, R.; Picard, D.; Smith, D. F. The
Hsp90-binding peptidylprolyl isomerase FKBP52 potentiates gluco-
corticoid signaling in vivo. EMBO J. 2003, 22, 1158−1167.
(15) Cameron, A. M.; Steiner, J. P.; Sabatini, D. M.; Kaplin, A. I.;
Walensky, L. D.; Snyder, S. H. Immunophilin FK506 binding protein
associated with inositol 1,4,5-trisphosphate receptor modulates
calcium flux. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 1784−1788.
(16) Shirane, M.; Nakayama, K. I. Inherent calcineurin inhibitor
FKBP38 targets Bcl-2 to mitochondria and inhibits apoptosis. Nat. Cell
Biol. 2003, 5, 28−37.
(32) DeLano, W. L. The PyMOL Molecular Graphics System; DeLano
Scientific: Palo Alto, CA, 2002.
(17) Ahearn, I. M.; Tsai, F. D.; Court, H.; Zhou, M.; Jennings, B. C.;
Ahmed, M.; Fehrenbacher, N.; Linder, M. E.; Philips, M. R. FKBP12
binds to acylated H-ras and promotes depalmitoylation. Mol. Cell
2011, 41, 173−185.
(18) Yang, W. M.; Inouye, C. J.; Seto, E. Cyclophilin A and FKBP12
interact with YY1 and alter its transcriptional activity. J. Biol. Chem.
1995, 270, 15187−15193.
(19) Ochocka, A. M.; Kampanis, P.; Nicol, S.; Allende-Vega, N.; Cox,
M.; Marcar, L.; Milne, D.; Fuller-Pace, F.; Meek, D. FKBP25, a novel
regulator of the p53 pathway, induces the degradation of MDM2 and
activation of p53. FEBS Lett. 2009, 583, 621−626.
(20) Jayaraman, T.; Brillantes, A. M.; Timerman, A. P.; Fleischer, S.;
Erdjument-Bromage, H.; Tempst, P.; Marks, A. R. FK506 binding
protein associated with the calcium release channel (ryanodine
receptor). J. Biol. Chem. 1992, 267, 9474−9477.
(21) Edlich, F.; Weiwad, M.; Wildemann, D.; Jarczowski, F.; Kilka, S.;
Moutty, M. C.; Jahreis, G.; Lucke, C.; Schmidt, W.; Striggow, F.;
Fischer, G. The specific FKBP38 inhibitor N-(N′,N′-
dimethylcarboxamidomethyl)cycloheximide has potent neuroprotec-
tive and neurotrophic properties in brain ischemia. J. Biol. Chem. 2006,
281, 14961−14970.
(22) Monaghan, P.; Bell, A. A Plasmodium falciparum FK506-binding
protein (FKBP) with peptidyl-prolyl cis−trans isomerase and
chaperone activities. Mol. Biochem. Parasitol. 2005, 139, 185−195.
(23) Bell, A.; Monaghan, P.; Page, A. P. Peptidyl-prolyl cis−trans
isomerases (immunophilins) and their roles in parasite biochemistry,
host−parasite interaction and antiparasitic drug action. Int. J. Parasitol.
2006, 36, 261−276.
(24) Marinec, P. S.; Chen, L.; Barr, K. J.; Mutz, M. W.; Crabtree, G.
R.; Gestwicki, J. E. FK506-binding protein (FKBP) partitions a
modified HIV protease inhibitor into blood cells and prolongs its
lifetime in vivo. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 1336−1341.
(25) Babine, R. E.; Bleckman, T. M.; Kissinger, C. R.; Showalter, R.;
Pelletier, L. A.; Lewis, C.; Tucker, K.; Moomaw, E.; Parge, H. E.;
Villafranca, J. E. Design, synthesis and X-ray crystallographic studies of
novel FKBP-12 ligands. Bioorg. Med. Chem. Lett. 1995, 5, 1719−1724.
(26) Kotaka, M.; Ye, H.; Alag, R.; Hu, G.; Bozdech, Z.; Preiser, P. R.;
Yoon, H. S.; Lescar, J. Crystal structure of the FK506 binding domain
of Plasmodium falciparum FKBP35 in complex with FK506.
Biochemistry 2008, 47, 5951−5961.
(27) Alag, R.; Shin, J.; Yoon, H. S. NMR assignments of the FK506-
binding domain of FK506-binding protein 35 from Plasmodium vivax.
Biomol. NMR Assignments 2009, 3, 243−245.
(28) Alag, R.; Qureshi, I. A.; Bharatham, N.; Shin, J.; Lescar, J.; Yoon,
H. S. NMR and crystallographic structures of the FK506 binding
domain of human malarial parasite Plasmodium vivax FKBP35. Protein
Sci. 2010, 19, 1577−1586.
(29) Kang, C. B.; Ye, H.; Yoon, H. R.; Yoon, H. S. Solution structure
of FK506 binding domain (FKBD) of Plasmodium falciparum FK506
binding protein 35 (PfFKBP35). Proteins 2008, 70, 300−302.
(30) Revill, W. P.; Voda, J.; Reeves, C. R.; Chung, L.; Schirmer, A.;
Ashley, G.; Carney, J. R.; Fardis, M.; Carreras, C. W.; Zhou, Y.; Feng,
L.; Tucker, E.; Robinson, D.; Gold, B. G. Genetically engineered
analogs of ascomycin for nerve regeneration. J. Pharmacol. Exp. Ther.
2002, 302, 1278−1285.
E
dx.doi.org/10.1021/ml400306r | ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX